Multicomponent Strategy for the Synthesis of Prostaglandin E2 Methyl

Jan 26, 2016 - ABSTRACT: Starting with four components, the enantioselective synthesis of prostaglandin E2 methyl ester has been achieved through a ...
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Multicomponent Strategy for the Synthesis of Prostaglandin E2 Methyl Ester under Anion Relay Chelation Control Kuan-Hsun Huang, Chun-Chieh Huang, and Minoru Isobe*,# Department of Chemistry, National Tsing Hua University, Hsinchu, 30013, Taiwan (ROC) S Supporting Information *

ABSTRACT: Starting with four components, the enantioselective synthesis of prostaglandin E2 methyl ester has been achieved through a highly stereoselective heteroatom-directed conjugate addition reaction and cyclopentanone ring cyclization as the key steps. This asymmetric strategy includes (i) an asymmetric Reformatsky reaction; (ii) conjugate addition of a chiral vinyllithium reagent; (iii) cyclization to form a sulfonylated cyclopentanone in one-pot; followed by (iv) allylation of the side chain. Four carbon−carbon bond-forming processes and three stereogenic centers were established, with the steps from (ii) to (iii) being achieved in a one-pot process.

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INTRODUCTION It has been the dream of synthetic chemists to be able to create multiple carbon−carbon bonds in a chemo- and stereoselective manner in a single reaction vessel. Domino or cascade reactions have been often used for such consecutive C−C bond formations to provide the target compound in highly controlled manner.1−9 Recently, further improvements in atom- and stepeconomy in domino reactions have been realized by protectionfree routes.10−12 Prostanoids are biosynthesized in the body from arachidonic acid by the action of COX enzymes13−15 and play various physiological roles including smooth muscle constriction or dilation, regulating inflammation, and platelet aggregation or disaggregation.16 Since the 1960s, many efforts on the chemical synthesis of prostaglandins have been reported, including the elegant strategies designed by Corey,17 Woodward,18 Stork,19 Fuchs,20 Noyori,21 Aggarwal,22 Hayashi,10 Nicolaou,23 and others. Because of the high demand of prostaglandins as drugs, there is still a necessity for the development of more efficient routes toward this class of compounds, based on new reactions and strategies. Herein we describe a four-component strategy for a highly economical synthesis of prostaglandins. In the course of tackling the syntheses of other complex natural products, we have developed a versatile C−C bondforming methodology that exerts acyclic stereocontrol via anion-relay, which we have coined heteroatom-directed © XXXX American Chemical Society

conjugate addition (HADCA). We have utilized this HADCA methodology effectively as a key step in the stereocontrolled total syntheses of maytansine,24 okadaic acid,25 tautomycin,26 and ciguatoxin.27 Complete stereochemical control in this C−C bond-forming reaction to obtain either diastereomer can be achieved through exploiting α- or β-chelation. This HADCA methodology also has the potential to synthesize the syn or anti complementary stereochemical arrays in either enantiomeric forms from similar starting materials (Scheme 1a).28,29 Due to allylic strain, i.e., A1,3-strain, chiral vinyl-sulfones 4 prefer to adopt a conformation A in which the trisubstituted carbon− carbon double bond is coplanar with the hydrogen atom at the C3 stereogenic carbon, in the ground state as well as in the transition state (Scheme 1b). Substrate 4 is known to react with MeLi·LiBr and undergo a subsequent Brook rearrangement (B → C), to give exclusively syn-product 5a within 10 min at −78 °C, with no observable concomitant formation of antiproduct 6. Quenching the reaction mixture with D2O/THF at −78 °C afforded the dideuterated compound 5b, suggesting that the precursor was the corresponding dianionic species 5c. The HADCA methodology has also been further engaged to undergo a domino cyclobutane-ring cyclization. A syn conjugate addition to 7 generated carbanion D, whose reactivity was Received: December 1, 2015

A

DOI: 10.1021/acs.joc.5b02735 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry Scheme 1. HADCA

should direct the addition of the vinyllithium derived from 15 through α-chelation control, leading to a syn-stereochemistry of 14. An asymmetric reduction of enone 16 is known to provide optically enriched 15.33 Vinylsulfone 17 could be synthesized from thioacetylene 18 via hydrosilylation.34 An asymmetric Reformatsky-type reaction would generate 18 from oxazolidinone 19 and aldehyde 20.

enhanced by a salt effect, and intramolecularly attacked the epoxide in an exo fashion (Scheme 1c).30−32 Since five-membered ring formation through endo epoxide opening was not observed for D at all, to yield a cyclopentane as found in the prostaglandin nucleus, it must be obtained by reaction with a different electrophilic group. We surmised that cyclopentanone formation for the synthesis of a prostaglandin like 9 required a substrate with a tert-butoxy-carbonyl functionality that would not be expected to compete with the vinylsulfone group for the C-nucleophile (Scheme 1d). The construction of the C12 stereocenter in a syn manner by HADCA could be directed by the neighboring C11-oxygen functionality through α-chelation. The reaction of carbanion intermediate E should terminate with C8−C9 bond formation to yield a cyclopentanone to access the synthesis of prostaglandins. Using HADCA as the central concept of a plan for the asymmetric synthesis of prostaglandin E2 (PGE2) methyl ester 12 is shown in Scheme 2. The alkylation of ketosulfone 14 with allylic halide 13 was envisioned to be the last C−C bondforming event. Cyclopentanone 14 with the correct stereochemistry would be expected to be obtained from alcohol 17 via HADCA of a vinyllithium reagent. The lithium alkoxide generated from the deprotonation of the hydroxyl group of 17

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RESULTS AND DISCUSSION First, to examine the proposed syntheic plan, racemic 17 was prepared in five steps from commercially available propargyl alcohol without any protection steps (Scheme 3). The dianion of propargyl alcohol was generated and trapped with thiosulfonate to provide 21, and the hydroxyl group of which was oxidized to the corresponding aldehyde. Since aldehyde 20 was not so stable, it was subjected directly to the Reformatsky reaction with t-butyl bromoacetate to produce rac-22. Alkyne rac-22 was converted to vinyl(silyl)sulfide rac-23 in a regio- and stereoselective manner using a dicobalt complex catalyst,34 and the sulfide was further oxidized to provide the racemic sulfone rac-17 (Scheme 3). The bulky tert-butoxycarbonyl group of rac-17 was installed to deter the nucleophile from attacking the carbonyl group as well as discouraging α-deprotonation, which might result in the elimination of the hydroxyl group, but the B

DOI: 10.1021/acs.joc.5b02735 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry Scheme 2. Retrosynthesis of Prostaglandin E2 Methyl Ester (PGE2) 12

Scheme 3. Synthesis of Racemic tert-Butyl C5-Ester rac-17

first step is deprotonation of OH so there should not be elimination. When we examined the HADCA reaction of rac-17, we observed a significant difference in the reactivity compared with 4. When MeLi·LiBr was employed as the nucleophile at −78 °C in THF, the reaction with 4 was 95% complete within 10 min (Scheme 1b), whereas the corresponding addition to rac-17 was not incomplete even after 18 h (Table 1, entry 1). Such an enormous difference in reactivity may be attributed to the different chelation structures of the two substrates. The reaction conditions of the HADCA to rac-17 were studied by changing the nucleophiles, salt additives, and temperatures, and the results are summarized in Table 1. Employing of 2.5 equiv of MeLi·LiBr in the reaction with rac-17 at −78 °C provided two products: O-silylated methyl adduct 24a and cyclization product 25a, together with unreacted rac-17 (entry 1). The addition of NaBr to the reaction mixture facilitated the cyclization slightly (entry 2). Upon raising the temperature from −78 to −20 °C, only the methyl addition and cyclization product 25a (Nu = Me) was obtained in 86% yield (entry 3). Using MeMgBr or MeMgCl as nucleophile resulted in no reaction and the recovery of most of rac-17 (entries 4, 5). The use of a vinyllithium reagent, generated from (E)-1-iodooct-1ene and t-BuLi at −78 °C, in the presence of 0.25 equiv of NaBr afforded 25b (Nu = −CHCHC6H13) upon warming to −20 °C. After 12 h, some unreacted rac-17 remained, but no

24b was observed (entry 6). However, the addition of 5 equiv of LiBr and 0.1 equiv NaBr resulted in complete HADCA but with partial cyclization, to give 24b and 25b (entry 7). The effect of the addition of LiBr might be to enhance the rate of nucleophilic addition and promote HADCA, whereas the addition of NaBr promoted cyclization. From previous studies of this salt effect,30,31 the optimum results were obtained with 2.5−5 equiv of LiBr and with 0.25 equiv of NaBr. In the event, the reaction of rac-17 in the presence of 5 equiv of LiBr and 0.25 equiv of NaBr facilitated both HADCA and cyclization to give only 25b in 82% yield (entry 8). Oct-1-yn-1-yllithium without NaBr as additive (MeLi·LiBr contains ca. 2.5 equiv of LiBr) reacted with rac-17 for 1 h to afford a mixture of 24c:25c in a 3:1 ratio (entry 9). But in the presence of NaBr as additive, a higher ratio (1:1) of cyclization product was observed (entry 10) with otherwise the same conditions. Prolonging the reaction time to 5 h at −20 °C led to complete cyclization giving exclusively 25c in 84% yield (entry 11). These studies of the HADCA cyclization prompted us to take on the challenge of accomplishing a one-pot, four-component synthesis (Scheme 5). This strategy required (Z)-silylsulfonyl enal 30, which was synthesized in four steps from propargyl alcohol as shown in Scheme 4. The same dianion generated from propargyl alcohol was trapped with phenyldimethylchlorosilane to give 26. Silylacetylene 26 was subjected to a hydromagnesiation reaction according to Sato’s titanocene-mediated C

DOI: 10.1021/acs.joc.5b02735 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry Table 1. Results of HADCA on Silylvinyl-Sulfone rac-17

a

Determined by 1H NMR analysis of the crude product. bYield of isolated product after column chromatography.

afforded 25b in 53% yield. Finally, the use of oct-1-yn-1yllithium under the same conditions provided 25c in 58% yield (Scheme 5). In each of these one-pot reactions, three C−C bonds were constructed with excellent stereoselectivity to give the substituted cyclopentanones 25a−c as single stereoisomers. The structure of 25b was deduced on the basis of NMR experiments, and 25a and 25c were assumed to have the same relative stereochemistry (for details, see SI). The completion of the synthesis of (±)-15-deoxy PGE2 36 from HADCA cyclization product 25b is shown in Scheme 6. Alkylation of 25b with allylic bromide 13 in the presence of K2CO3 and NaI (cat.) in DMF afforded a diastereomeric mixture of 33, which was further treated with SmI2 in mixed THF/MeOH solvent (1:1) at −78 °C to give 34 as a single isomer. It was treated with HF·pyridine in acetonitrile at 0 °C to give (±)-15-deoxy PGE2 methyl ester 35 in 74% yield. Hydrolysis with PPL in pH 7 buffer afforded (±)-15-dehydroxy PGE2 36 in 85% yield. Thus, the overall yield of 36 was 42% from 25b over four steps. In order to understand the mechanism of the HADCA reaction of rac-17 with (E)-oct-1-en-1-yllithium at −78 °C, the reaction was quenched with D2O/THF after 1 h at −50 °C. The product mixture contained unreacted rac-17 (20%), α,α-di-D-24b (30% yield, 93% D-incorporation) and 25b (20%) (Scheme 7). The stereoselective HADCA cyclization reaction and the effects of the salts are explained as follows: The A1,3-strain in

Scheme 4. Synthesis of Aldehyde 30

protocol35 and trapped by thiosulfone to afford thioether 27, along with 28 in a ratio of 4.9:1. Oxidation of the sulfide in the mixture with m-CPBA and separation afforded hydroxysulfone 29, which was oxidized with MnO2 to afford aldehyde 30 (Scheme 4). The one-pot assembly of cyclopentanones was implemented as follows: First, lithium enolate 32 was prepared by the deprotonation of t-butyl acetate 31 at −78 °C and was treated with aldehyde 30 to give aldol intermediate A, which is analogous to the lithium alkoxide of rac-17. After the addition of MeLi·LiBr and a catalytic amount of NaBr at −78 °C, the reaction temperature was gradually raised to −20 °C to induce HADCA and cyclization. Protonation upon workup afforded 25a in 57% yield. Similarly, the treatment of aldol intermediate A with (E)-oct-1-en-1-yllithium, LiBr (3 equiv), and NaBr (0.3 equiv) D

DOI: 10.1021/acs.joc.5b02735 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry Scheme 5. Three C−C Bond Formations in One-Pot Syntheses of Racemic 25a−c

Scheme 6. Racemic Synthesis of 15-Deoxy PGE2 36

Scheme 7. Deuterium-Labeling Experiments for HADCA Reaction

Scheme 8. A Plausible Reaction Mechanism on Salt Effect to Chelation Controlled HADCA Anion Relay Cyclizationa

a

The coordinations between Li and THF (solvent) are not shown.

rac-17 facilitated high stereocontrol in the HADCA reaction, by chelation of the vinyllithium via the lithium alkoxide, such that the nucleophile added syn with respect to the α-oxygen

(Scheme 8). LiBr, possibly reacting as a Lewis acid, enhanced the rate of conjugate addition to give B. B must then undergo a conformational change to C, in order to proceed with the E

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The Journal of Organic Chemistry

Table 2. Asymmetric Samarium-Reformatsky Reaction of Chiral α-Bromoacetyl-2-oxazolidinones 37a−e with the Aldehyde 20 To Form 38a−e, Leading to Selective Synthesis of (R)-Alcohol Ester (R)-21

a

Ratio was determined by crude 1H NMR spectrum. bYield of isolated product after column chromatrography.

Scheme 9. Synthesis of Chiral Vinylsulfone (R)-(+)-17 from (R)-22

Brook rearrangement to yield D. The α,α-dilithiated state of D found support from the deuteration experiments (Scheme 7). Because the rigid Li chelation in E could prevent or slow down the subsequent cyclization, the addition of Na+ (less covalent ion than Li+) led to metal exchange with Li+ and promoted cyclization via F to give keto−enolate G. Work up provided cyclopentanone 25 as a single stereoisomer ( Scheme 8). Unfortunately, attempts to induce the alkylation of the side chain in one pot from G failed to occur under these conditions. Next, we approached the asymmetric synthesis of PGE2 methyl ester 12. An asymmetric samarium Reformatsky-type reaction was employed to install the C11 stereogenic center by using a chiral oxazolidinone and aldehyde 20. Screening five chiral auxiliaries (Xc in Table 2) as reported by Fukuzawa36 yielded diastereomeric products of very different ratios as found from the NMR data, summarized in Table 2. In entries 1−4, the chemical yields of the products are good, but the diastereomeric ratios of the products are low. However, in the case of 4-isopropyl-5,5-diphenyl-2-oxazolidine 19, product 18 was obtained as a single stereoisomer in 88% yield (entry 5). The absolute configuration of 38a was assigned using the Mosher− Kusumi protocol37 and further confirmed by converting to the corresponding alcohol, 22. The t-butyl ester derivative was deduced to be (R)-22 based on the positive sign of its optical rotation and (S)-22 when it has a negative rotation. Assignments of the stereochemistries of 38b−d were based on NMR analysis and by comparison with the optical rotations of 22 (see SI).

Alkyne (R)-22 was hydrosilylated with phenyldimethylsilane using a cobalt−acetylene complex as a catalyst, to give (R)-23 in high regio- and stereoselectivity. The sulfide was oxidized with m-CPBA to the corresponding sulfone (R)-(+)-17 (Scheme 9). The one-pot HADCA cyclizations of (R)-17 with the vinyllithium derived from iodide (S)-15 are summarized in Table 3. When this reaction was carried out in THF, low yields of (−)-14 were obtained in the presence of LiBr, whether or not NaBr was an additive (entries 1 and 2). When the less polar Et2O was employed as the reaction solvent and in the presence of LiBr (5 equiv) and NaBr (0.25 equiv), product (−)-14 was obtained in 20% yield when the reaction was performed at −78 to −20 °C for 12 h (entry 3). In the absence of NaBr in Et2O, however, (−)-14 was obtained in an even higher yield of 58% and with the correct stereochemistry as deduced from the NOE experiments (entry 4). These LiBr-NaBr effects found in Et2O as solvent were different from their effects on reactions conducted in THF as solvent (e.g., Table 1). Such a difference might be due to the presence of the additional oxygen atom in compound 15, which could participate in the chelation during the HADCA cyclization reaction. The (−)-PGE2 methyl ester 12 was synthesized from (−)-14 by alkylation with 13 to give 39 as shown in Scheme 10, under conditions similar to those for the preparation of 25b (Scheme 6). Subsequent desulfonylation with SmI2 was implemented in a mixed THF/MeOH solvent at −78 °C to give (−)-40. Final deprotection of the silyl ether with HF·pyridine in acetonitrile at 0 °C afforded PGE2 methyl ester 12 in 42% overall yield from F

DOI: 10.1021/acs.joc.5b02735 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry Table 3. Synthesis of (−)-14 Having 15-(S)-Hydroxyl Group

Scheme 10. Synthesis of PGE2 Methyl Ester (−)-12

High-resolution mass spectra (HRMS) were recorded on a ESI/FTMS mass spectrometer and reported in m/z. Infrared (IR) spectra were recorded on a FT-IR spectrometer and reported in wavenumbers (cm−1). Optical rotations were measured on a digital polarimeter. HPLC analysis was carried out with a variable-wavelength detector. All reactions were performed using oven-dried glassware under an atmosphere of dry nitrogen. Nonaqueous reagents were transferred under argon by syringe. Organic solutions were concentrated under reduced pressure using a rotary evaporator. Reactions were monitored by thin-layer chromatography on 0.25 mm Silica Gel 60 F254 precoated glass plates using UV light to visualize or ammonium molybdate tetrahydrate solution as stain. Silica Gel 60 (particle size 40−63 μm) was used for flash column chromatography. Dry THF was distilled from sodium metal with benzophenone under an N2 atmosphere. Dry Et2O and CH2Cl2 were distilled from CaH2 under an N2 atmosphere. All other commercial reagents were used as received. 3-(Phenylthio)prop-2-yn-1-ol (21). A solution of propargyl alcohol (11.6 mL, 220 mmol) in THF (50 mL) was cooled to −78 °C, to which n-BuLi (2.4 M in hexanes, 184 mL, 440 mmol) was added dropwise. After stirring for 1 h at −78 °C, PhSSO2Ph (45.0 g, 180 mmol) in THF (50 mL) was added dropwise. The reaction was slowly warmed to −50 °C and stirred for 1 h. The reaction mixture was warmed to −20 °C and stirred for another 1 h. The reaction mixture was quenched with an ice-cooled saturated solution of NH4Cl (500 mL). The aqueous layer was extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (20% EtOAc/ hexane, Rf = 0.20) to provide alcohol 21 (14.8 g, 50%) as a pale yellow oil. 21: Rf = 0.20 (20% EtOAc/hexane); IRvmax (neat, cm−1): 3342, 3060, 2911, 2855, 1582, 1478, 1441, 1063, 995, 737, 587;1H NMR

(−)-14. The stereochemistry was confirmed by NOESY as shown in 40a, and the specific rotation of PGE2 methyl ester 12 ([α]24 D, 65.9 (c 0.30, MeOH)) was in agreement with literature report 20 ([α]24 D , 71.7 (c 1.04, MeOH)).

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CONCLUSION The asymmetric total synthesis of PGE2 has been achieved in a one-pot reaction plus three steps. The synthesis starts with the (R)-silylvinyl sulfone 17, through (−)-14, to afford (−)-12 in 4 steps and 24.4% overall yield. The key feature in this synthesis is a highly selective HADCA reaction followed by spontaneous cyclization under substrate control in one-pot reaction. All of the four C−C bond formation processes were successively implemented with high stereoselectivity starting from the four acyclic components. A strictly one-pot synthesis of prostaglandins may be realized along these lines in the future.

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EXPERIMENTAL SECTION

General Information. Proton nuclear magnetic resonance (1H NMR) spectra were recorded on a 400 MHz and a 600 MHz NMR spectrometer. NMR characterization is reported as follows: Chemical shifts are reported as δ values referenced to CHCl3 (7.24), integration, multiplicity (s = singlet, d = doublet, t= triplet, q = quartet, br = broad, m = multiplet or unresolved, ABq = AB quartet), coupling constants in Hz, and assignment. Carbon nuclear magnetic resonance (13C NMR) spectra were recorded on a 100 and 150 MHz spectrometers. Chemical shifts are reported as δ values and referenced to CHCl3 (77.00). G

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The Journal of Organic Chemistry

(CH × 2), 127.9 (CH × 2), 128.9 (CH × 2), 129.9 (CH), 132.9 (CH), 134.3 (CH × 2), 135.0 (C), 141.9 (C), 145.4 (C), 157.7 (CH), 171.0 (C); HRMS (ESI): calcd for [C23H30O5SSi + Na]+ 469.1481; found 469.1474. General procedure for HADCA of various nucleophiles to rac-17 (Table 1). HADCA with MeLi·LiBr. The tert-butyl ester of the vinyl silyl sulfone rac-17 (1 equiv) and NaBr (equiv see Table 1) in THF (0.1 M) were added to the MeLi·LiBr complex (2.21 M in Et2O, equiv see Table 1) at −78 °C under argon atmosphere. The reaction mixture was stirred at −78 °C or warmed to −20 °C in 1 h and stirred for 4 h at −20 °C as indicated in Table 1. The reaction mixture was poured into ice-cooled saturated solution of NH4Cl. The aqueous layer was extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO4, filtered off, and concentrated in vacuo. The residue was purified by flash column chromatography to provide the 24a and 25a as a colorless oil. tert-Butyl (3R,4S)-3-((dimethyl(phenyl)silyl)oxy)-4-methyl-5(phenylsulfonyl)pentanoate (24a). Column chromatography of the mixture (combined entries 1 and 2) afforded small amount of pure 24a and mixture fraction. 24a: Rf = 0.60 (30% EtOAc/hexane); IRvmax (neat, cm−1): 3069, 2977, 2933, 1731, 1587; 1H NMR (400 MHz, CDCl3): δ 0.307 (3H, s), 0.313 (3H, s), 1.03 (3H, d, J = 7.2 Hz), 2.16−2.30 (3H, m), 2.73 (1H, dd, J = 13.9, 9.5 Hz), 3.22 (1H, dd, J = 13.9, 3.0), 4.18 (1H, ddd, J = 8.0, 4.8, 4.2 Hz), 7.30−7.38 (3H, m), 7.47−7.54 (4H, m), 7.57−7.62 (1H, m), 7.78−7.80 (2H, m); 13C NMR (100 MHz, CDCl3): δ −1.4 (CH3), −1.3 (CH3), 14.6 (CH3), 28.0(CH3 × 3), 34.1 (CH), 39.7 (CH2), 58.5 (CH2), 72.0 (CH), 80.8 (C), 127.79 (CH × 2), 127.80 (CH × 2), 129.7 (CH), 133.1 (CH × 2), 133.44 (CH × 2), 137.6 (C), 140.1 (C), 170.3 (C); HRMS (ESI): calcd for [C24H34O5SSi + H]+ 463.1969; found 463.1967. (2R,3S,4R)-4-((Dimethyl(phenyl)silyl)oxy)-3-methyl-2(phenylsulfonyl)cyclopentanone (25a). According to the general procedure, rac-17 (130 mg) was converted to 25a (98 mg) in 86% yield as a colorless oil (entry 3, Table 1). Rf = 0.50 (30% EtOAc/ hexane); IRvmax (neat, cm−1): 3069, 2929, 2965, 1755, 1586; 1H NMR (400 MHz, CDCl3): δ 0.370 (3H, s), 0.386 (3H, s), 1.21 (3H, d, J = 6.4 Hz), 2.35−2.37 (2H. m), 2.70−2.80 (1H, m), 3.32 (1H, d, J = 10.4 Hz), 3.68−3.74 (1H, m), 7.33−7.42 (3H, m), 7.50−7.56 (4H, m), 7.64−7.67 (1H, m), 7.83−7.85 (2H, m); 13C NMR (100 MHz, CDCl3): δ −1.7 (CH3), −1.4 (CH3), 17.5 (CH3), 41.9 (CH), 48.4 (CH2), 73.3 (CH), 75.8 (CH), 128.0 (CH × 2), 129.1 (CH × 2), 129.17 (C), 129.24 (CH × 2), 130.1 (CH), 133.4 (CH × 2), 134.2 (CH), 136.7 (C), 202.2 (C); HRMS (ESI): calcd for [C20H24O4SSi + H]+ 389.1237; found 389.1241. HADCA with octen-1-yl Lithium. To a solution of (E)-1-iodoocat1-ene were added LiBr, and NaBr (equiv see Table 1) in THF (0.1 M) and tert-butyllithium (1.65 M in pentane, equiv see Table 1) at −78 °C over 10 min under argon atmosphere. The reaction mixture was stirred at −78 °C for additional 15 min. (Note: tert-butyllithium with THF form a bright yellow complex at −78 °C). The excess tert-butyllithium was removed by addition of one or two drops of vinyl iodide to the solution mixture. To this solution was added tert-butyl ester of the silylvinyl sulfone rac-17 (1 equiv) in THF (1.0 M). The resulting mixture was warmed to −20 °C in 1 h and stirred for 11 h at −20 °C. The reaction mixture was poured into ice-cooled saturated NH4Cl solution. The aqueous layer was extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO4, filtered off and concentrated in vacuo. The residue was purified by flash column chromatography to provide 24b and 25b as a colorless oil. ( 3 R, 4 S , E )- t e r t - B ut y l- 3 - ( ( di m e th y l ( p h e n y l ) s il y l) o x y ) - 4 ((phenylsulfonyl)methyl)dodec-5-enoate (24b). Column chromatography of the mixture (entry 7: started from 368 mg rac-17) afforded small amount of pure 24b (46 mg) and mixture fraction. 24b: Rf = 0.50 (20% EtOAc/hexane); IRvmax (neat, cm−1): 3069, 2957, 2928, 2856; 1H NMR (400 MHz, CDCl3): δ 0.35 (3H, s), 0.37 (3H, s), 0.86 (3H, t, J = 6.8 Hz), 1.22−1.26 (8H, m), 1.38 (9H, s), 1.84−1.85 (2H, br), 2.18 (1H, ABq, d, J = 15.5, 7.6 Hz), 2.28 (1H, ABq, d, J = 15.5, 5.6 Hz), 2.65 (1H, m), 2.98 (1H, dd, J = 14.0, 8.8), 3.22 (1H, dd, J = 14.0, 4.0 Hz), 4.19−4.23 (1H, m), 5.05 (1H, ddt, J = 15.2, 8.8, 1.2 Hz), 5.28 (1H, dt, J = 15.2, 6.8 Hz), 7.31−7.39 (3H, m), 7.46−7.53

(400 MHz, CDCl3): δ 2.61 (1H, br), 4.47 (2H, s), 7.19−7.24 (1H, m), 7.29−7.34 (2H, m), 7.40−7.43 (2H, m); 13C NMR (100 MHz, CDCl3): δ 51.9 (CH2), 7.29 (C), 97.5 (C), 126.5 (CH × 2), 126.8 (CH), 129.3 (CH × 2), 132.3 (C); HRMS (ESI): calcd for [C9H8OS + H]+ 165.0369; found 165.0369. tert-Butyl 3-hydroxy-5-(phenylthio)pent-4-ynoate (rac-22). To a solution of alcohol 21 (6123 mg, 37.29 mmol) in DCM (370 mL) was added MnO2 (64.79 g, 745 mmol) at room temperature. The reaction mixture was stirred for 2 h and filtered. The filtrate was dried over MgSO4 and concentrated in vacuo to obtain the crude aldehyde product 20. Crude aldehyde 20 was dissolved in THF (37 mL) and used in the next reaction without further purification. To a suspension of Zn dust (18.28 g, 279.6 mmol) and a catalytic amount of I2 in THF was added t-butyl bromoacetate (10.91 g, 55.93 mmol) over 30 min at room temperature under an argon atmosphere. The reaction mixture was stirred for 30 min at room temperature and then heated under reflux for 1 h. After cooling to 0 °C, aldehyde 20 in THF was added dropwise at 0 °C to the pale green solution. The reaction mixture was stirred at 0 °C for 1 h before pouring into an ice-cooled saturated solution of NH4Cl (300 mL). The aqueous layer was extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography to provide alcohol 22 (5.89 g, 56% over two steps) as a colorless oil. 22: Rf = 0.4 (10% EtOAc/hexane); IRvmax (neat, cm−1): 3435, 3060, 2978, 2931, 2186, 1727, 1583; 1H NMR (400 MHz, CDCl3): δ 1.46 (9H, s), 2.72−2.74 (2H, m), 3.36 (1H, d, J = 6.8 Hz), 4.88 (1H, ddd, J = 6.8, 6.4, 6.4 Hz), 7.18−7.22 (1H, m), 7.29−7.33 (2H, m), 7.37− 7.40 (2H, m); 13C NMR (100 MHz, CDCl3): δ 27.9 (CH3 × 3), 42.7 (CH2), 59.7 (CH), 72.0 (C), 81.9 (C), 98.0 (C), 126.2 (CH × 2), 126.5 (CH), 129.1 (CH × 2), 132.1 (C), 170.5 (C); HRMS (ESI): calcd for [C15H18O3S + Na]+ 301.0874; found 301.0871. tert-Butyl (Z)-5-(Dimethyl(phenyl)silyl)-3-hydroxy-5(phenylthio)pent-4-enoate (rac-23). The dicobalthexacarbonyl complex of 2-methyl-butyn-2-ol (1.0 M in DCM, 566 mL) was added to a mixture of thiophenylacetylene 22 (1.58 g, 5.67 mmol) and dimethylphenylsilane (855 mg, 6.23 mmol) in dry 1,2-dichloroethane (56 mL). The mixture was heated to 80 °C and stirred for 2 h. After the reaction mixture was cooled to room temperature, the solvent was removed in vacuo. The residue was washed with cold TBAF in water and brine, then purified by chromatography (10% EtOAc/hexane) to afford vinylsilane 23 (188 mg, 80%) as a colorless oil. 23: Rf = 0.20 (10% EtOAc/hexane); IRvmax (neat, cm−1): 3490, 3069, 2978, 1725, 1590; 1H NMR (400 MHz, CDCl3): δ 0.21 (3H, s), 0.24 (3H, s), 1.42 (9H, s), 2.44 (1H, d, J = 7.6 Hz), 2.45 (1H, d, J = 4.4 Hz), 3.41 (1H, d, J = 4.4 Hz), 5.13 (1H, dddd, J = 7.6, 6.8, 4.4, 4.4 Hz), 6.47 (1H, d, J = 6.8 Hz), 7.09−7.17 (3H, m), 7.26−7.36 (4H, m), 7.40−7.42 (2H, m); 13 C NMR (100 MHz, CDCl3): δ −2.6 (CH3), −2.5 (CH3), 28.1 (CH3 × 3), 41.2 (CH2), 66.9 (CH), 81.6 (C), 126.2 (CH), 127.7 (CH × 2), 128.7 (CH × 2), 129.2 (CH), 129.7 (CH × 2), 133.9 (CH × 2), 134.9 (C), 135.8 (C), 136.9 (C), 152.3 (CH), 171.7 (C); HRMS (ESI): calcd for [C23H30O3SSi + Na]+ 437.1577; found 437.1578. tert-Butyl (Z)-5-(Dimethyl(phenyl)silyl)-3-hydroxy-5(phenylsulfonyl)pent-4-enoate (rac-17). To a solution of vinylsilane 23 (1.62 g, 3.91 mmol) in DCM (39 mL) at 0 °C were added m-CPBA (2.41 g, 9.77 mmol, 70% of purity) and NaHCO3 (1.64 g, 19.54 mmol). The reaction was stirred at 0 °C for 1 h, then quenched with 1 N Na2S2O3 (40 mL). The aqueous layer was extracted with DCM (30 mL × 3). The combined organic layers were washed with 1 N NaHCO3 solution (30 mL), dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (20% EtOAc/hexane) to provide alcohol rac-17 (1.34 g, 77%) as a white solid. rac-17: Mp: 83−84 °C (recrystallization from EtOAc/hexane); Rf = 0.25 (20% EtOAc/hexane); IRvmax (neat, cm−1): 3490, 3069, 2978, 1725, 1590; 1H NMR (400 MHz, CDCl3): δ 0.52 (6H, s), 1.41 (9H. s), 2.43 (1H, ABq, d, J = 16.7, 8.0 Hz), 2.51 (1H, ABq, d, J = 16.7, 4.0 Hz), 3.54 (1H, d, J = 4.0 Hz), 5.37 (1H, ddd, J = 8.4, 8.0, 4.0 Hz), 6.46 (1H, d, J = 8.4 Hz), 7.27−7.38(5H, m), 7.42−7.56 (5H, m); 13C NMR (100 MHz, CDCl3): δ −2.2 (CH3), −2.1 (CH3), 28.0 (CH3 × 3), 41.1 (CH2), 65.4 (CH), 81.6 (C), 126.9 H

DOI: 10.1021/acs.joc.5b02735 J. Org. Chem. XXXX, XXX, XXX−XXX

Article

The Journal of Organic Chemistry (4H, m), 7.56−7.60 (1H, m), 7.73−7.75 (2H, m); 13C NMR (100 MHz, CDCl3): δ −1.4 (CH3), −1.2 (CH3), 14.1(CH3), 22.6 (CH2), 28.0 (CH3 × 3), 28.8 (CH2), 28.9 (CH2), 31.6 (CH2), 32.5 (CH2), 40.4 (CH2), 43.2 (CH), 57.2 (CH2), 72.0 (CH), 80.7 (C), 125.6 (CH), 127.8 (CH × 2), 128.0 (CH × 2), 129.0 (CH × 2), 129.7 (CH), 133.3 (CH), 133.5 (CH × 2), 135.7(CH), 137.6 (C), 140.0 (C), 170.2 (C); HRMS (ESI): calcd for [C31H46O5SSi + Na]+ 581.2733; found 581.2731. (2R,3S,4R)-4-((Dimethyl(phenyl)silyl)oxy)-3-((E)-oct-1-en-1-yl)-2(phenylsulfonyl)cyclopentanone (25b). According to the general procedure, rac-17 (248 mg) was converted to 25b (220 mg) in 82% yield as a colorless oil (entry 8, Table 1). Rf = 0.38 (20% EtOAc/ hexane); IRvmax (neat, cm−1): 3069, 2956, 2927, 2855, 1756, 1586; 1H NMR (600 MHz, CDCl3): δ 0.332 (3H, s), 0.335 (3H, s), 0.88 (3H, t, J = 7.2 Hz), 1.23−1.28 (8H, m), 1.85−1.87 (2H, m), 2.45 (1H, ABq, d, J = 17.1, 6.9 Hz), 2.49 (1H, ABq, d, J = 17.1, 10.1 Hz), 3.21−3.25 (1H, m), 3.53 (1H, d, J = 9.8 Hz), 3.84−3.88 (1H, m), 5.10 (1H, ddt, J = 16.2, 8.4, 1.4 Hz), 5.45 (1H, dtd, J = 16.2, 6.6, 0.6 Hz), 7.33−7.40 (3H, m), 7.48−7.54 (4H, m), 7.61−7.64 (1H, m), 7.82−7.84 (2H, m); 13 C NMR (100 MHz, CDCl3): δ −1.5 (CH3), −1.3 (CH3), 14.1 (CH3), 22.6 (CH2), 28.7 (CH2), 28.9 (CH2), 31.7 (CH2), 32.4 (CH2), 48.3 (CH2), 50.0 (CH), 71.9 (CH), 74.3 (CH), 126.8 (CH), 127.9 (CH × 2), 129.0 (CH × 2), 129.1 (CH x2), 130.0 (CH), 133.5 (CH × 2), 134.0 (CH), 135.2 (CH), 136.8 (C), 138.2 (C), 201.7 (C); HRMS (ESI): calcd for [C27H36O4SSi + Na]+ 507.2001, found 507.1998. HADCA with octyn-1-yl Lithium. To a mixture of oct-1-yne and NaBr (equiv see Table 1) in THF (0.1 M) was added MeLi·LiBr complex (2.21 M in Et2O, equiv see Table 1) at −78 °C under argon atmosphere. This mixture was stirred at −78 °C for 1 h. To this solution was added tert-butyl ester of the silylvinyl sulfone rac-17 (1 equiv) in THF (1.0 M). The resulting mixture was warmed to −20 °C in 1 h and stirred for additional 4 h at −20 °C. The reaction mixture was poured into ice-cooled saturated solution of NH4Cl. The aqueous layer was extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO4, filtered off, and concentrated in vacuo. The residue was purified by flash chromatography to provide the 24c and 25c as a colorless oil. tert-Butyl (3R,4S)-3-((dimethyl(phenyl)silyl)oxy)-4((phenylsulfonyl)methyl)dodec-5-ynoate (24c). According to the general procedure, rac-17 (46 mg) was converted to 24c (25 mg) in 44% yield and 25c (8 mg, 16%) (entry 9, Table 1). 24c: Rf = 0.63 (20% EtOAc/hexane); IRvmax (neat, cm−1): 3069, 2957, 2931, 2858, 1731, 1587; 1H NMR (400 MHz, CDCl3): δ 0.357 (3H, s), 0.364 (3H, s), 0.86 (3H, t, J = 6.8 Hz), 1.18−1.30 (8H, m), 1.38 (9H, s), 1.84−1.88 (2H, m), 2.23 (1H, dd, J = 15.6, 8.8 Hz), 2.59 (1H, dd, J = 15.6, 3.6 Hz), 2.98−3.03 (1H, m), 3.08 (1H, dd, J = 13.6, 10.0 Hz), 3.40 (1H, dd, J = 13.6, 10.0 Hz), 4.33 (1H, ddd, J = 8.8, 3.6, 3.6 Hz), 7.32−7.38 (3H, m), 7.47−7.55 (4H, m), 7.57−7.61 (1H, m), 7.83− 7.85 (2H, m); 13C NMR (100 MHz, CDCl3): δ −1.27 (CH3), −1.22 (CH3), 14.0 (CH3), 18.6 (CH2), 22.5 (CH2), 28.1 (CH3 × 3), 28.4 (CH2), 29.7 (CH2), 31.3 (CH2), 33.5 (CH), 39.9 (CH2), 56.2 (CH2), 70.6 (CH), 76.2 (C), 80.8 (C), 85.9 (C), 127.9 (CH × 2), 128.4 (CH × 2), 129.0 (CH × 2), 129.7 (CH), 13.47 (CH), 133.52 (CH × 2), 137.4 (C), 139.8 (C), 170.3 (C); HRMS (ESI): calcd for [C31H44O5SSi + Na]+ 579.2570, found 579.2571. (2R,3S,4R)-4-((Dimethyl(phenyl)silyl)oxy)-3-(oct-1-yn-1-yl)-2(phenylsulfonyl)cyclopentanone (25c). According to the general procedure, rac-17 (73 mg) was converted to 25c (66 mg) in 84% yield (entry 11, Table 1). Rf = 0.50 (20% EtOAc/hexane); IRvmax (neat, cm−1): 3068, 2930, 2857, 1762, 1586; 1H NMR (400 MHz, CDCl3): δ 0.39 (3H, s), 0.42 (3H, s), 0.88 (3H, t, J = 7.2 Hz), 1.18−1.39 (8H, m), 1.95 (2H, td, J = 6.8, 2.0 Hz), 2.46−2.49 (2H, m), 3.47 (1H, ddt, J = 9.6, 7.6, 2.0 Hz), 3.74 (1H, d, J = 9.6 Hz), 4.12 (1H, ddd, J = 9.2, 7.6, 7.6 Hz), 7.33−7.41 (3H, m), 7.52−7.56 (4H, m), 7.62−7.67 (1H, m), 7.88−7.90 (2H, m); 13C NMR (100 MHz, CDCl3): δ −1.6 (CH3), −1.2 (CH3), 14.1 (CH3), 18.6 (CH2), 22.5 (CH2), 28.46 (CH2), 28.54 (CH2), 31.3 (CH2), 39.5 (CH), 48.0 (CH2), 72.9 (CH), 75.2 (CH), 77.4 (C), 84.2 (C), 127.9 (CH2), 129.1 (CH × 2), 129.2 (CH × 2), 130.0 (CH), 133.5 (CH × 2), 134.2 (CH), 136.7 (C),

138.2 (C), 200.7 (C); HRMS (ESI): calcd for [C27H34O4SSi + Na]+ 505.1839; found 505.1839. (Z)-3-(Dimethyl(phenyl)silyl)-3-(phenylsulfonyl)prop-2-en-1ol (29). Alkyne 26 was prepared from progargyl alcohol according to the literature.38 To Cp2TiCl2 (2.40 g, 9.64 mmol) in dry Et2O (50 mL) was added iPrMgBr (2.46 M in Et2O, 89.0 mL, 218.0 mmol) at 0 °C, and this suspension was stirred for 15 min. The silylacetylene 26 (16.58 g, 87.12 mmol) in Et2O (87 mL) was added via cannula at 0 °C and then warmed to room temperature with stirring for 6 h. After cooling to 0 °C, PhSSO2Ph (28.53 g, 130.7 mmol) in THF (70 mL) was added into the reaction mixture in dropwise. This mixture was then heated to reflux for 5 h before pouring into ice-cooled saturated solution of NH4Cl (500 mL). The aqueous layer was extracted with Et2O (200 mL × 3). The combined organic layers were washed with brine, dried over MgSO4, filtered off, and concentrated in vacuo. The residue was purified by flash column chromatography (10% EtOAc/ hexane) to provide the inseparable silylvinyl phenyl sulfide 27 and vinylsilane 28 in 20.0 g (ratio 27/28 = 4.9/1). The silylvinyl sulfide mixture in DCM (650 mL) was added to m-CPBA (41.0 g, 166 mmol, 70% of purity) and NaHCO3 (2.80 g, 333 mmol) at 0 °C and then warmed to room temperature with stirring for 1 h. The reaction mixture was quenched with 1 N Na2S2O3 (600 mL). The aqueous layer was extracted with DCM (200 mL × 3). The combined organic layer was washed 1 N NaHCO3 solution (100 mL), dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (30% EtOAc/hexane) to provide the alcohol 29 (1.93 g, 67%) as a pale yellow solid. 29: Mp: 82−83 °C (recrystallization from EtOAc/hexane); Rf = 0.25 (30% EtOAc/ hexane); IRvmax (neat, cm−1): 3501, 3069, 3002, 2958, 2902, 1589; 1H NMR (400 MHz, CDCl3): δ 0.55 (6H, s), 4.57 (2H, d, J = 4.8 Hz), 6.62 (1H, t, J = 4.8 Hz), 7.30−7.38 (5H, m), 7.46−7.53 (5H, m); 13C NMR (100 MHz, CDCl3): δ −2.2 (CH3 × 2), 60.7 (CH2), 126.9 (CH x2), 127.9 (CH × 2), 128.8 (CH × 2), 129.7 (CH), 132.9 (CH), 134.4 (CH), 135.1 (C), 141.7 (C), 144.9 (C), 158.8 (CH); HRMS (ESI): calcd for [C17H20O3SSi + Na]+ 355.0795; found 355.0797. (Z)-3-(Dimethyl(phenyl)silyl)-3-(phenylsulfonyl)acrylaldehyde (30). To a solution of alcohol 29 (1.022 g, 3.075 mmol) in DCM (30 mL) was added MnO2 (2.672 g, 30.70 mmol) at room temperature. The reaction mixture was stirred for 2 h and filtered. The filtrates were dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography (20% EtOAc/ hexane) to yield aldehyde 30 (904 mg, 89%) as a yellow color oil, which was unstable. We used it immediately after spectra measurements. 29: Rf = 0.35 (20% EtOAc/hexane); IRvmax (neat, cm−1): 3070, 3002, 2959, 2901, 1684, 1583;1H NMR (400 MHz, CDCl3): δ 0.56 (6H, s), 6.41 (1H, d, J = 6.0 Hz), 7.29−7.33 (2H, m), 7.35−7.41 (6H, m), 7.52−7.54 (2H, m), 10.61 (1H, d, J = 6.0 Hz); 13C NMR (100 MHz, CDCl3): δ −2.6 (CH3 × 2), 127.3 (CH × 2), 128.2 (CH × 2), 129.2 (CH × 2), 130.2 (CH), 133.5 (CH), 134.3 (CH × 2), 140.8 (C), 146.6 (CH), 160.00 (C), 160.02 (C), 190.9 (CH); HRMS (ESI): calcd for [C17H18O3SSi + Na]+ 353.0638; found 353.0635. Three-Components in One-Pot Reaction: Aldol/HADCA/ Cyclization (Scheme 5). Aldol/HADCA/Cyclization with MeLi·LiBr. To a solution of diisopropylamine (59 mg, 0.581 mmol), NaBr (12 mg, 0.121 mmol) in THF (5.0 mL) at 0 °C was added n-BuLi (2.45 M in hexanes, 0.237 mL, 0.581 mmol) under an argon atmosphere and stirred for 15 min. Then the solution was cooled to −78 °C and was mixed with tert-butyl acetate 31 (62 mg, 0.53 mmol) in THF (0.5 mL), and this mixture was stirred at −78 °C for 1 h. The resulting solution of the enolate of tert-butyl acetate was added dropwise in a solution of aldehyde 30 (160 mg, 0.484 mmol) in THF (0.5 mL) with stirring in 30 min at −78 °C. To this mixture was further added (dropwise) the MeLi·LiBr solution (2.21 M in Et2O, 0.438 mL, 0.968 mmol). The reaction mixture was kept at −20 °C in 1 h with stirring for 4 h. The reaction mixture was quenched with aqueous saturated NH4Cl (50 mL) solution, and the aqueous layer was extracted with EtOAc (10 mL × 3). The combined organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography to obtain cyclopentanone 25a (107 mg, 57%) as a colorless oil. I

DOI: 10.1021/acs.joc.5b02735 J. Org. Chem. XXXX, XXX, XXX−XXX

Article

The Journal of Organic Chemistry

purified by flash column chromatography and eluted by 20% EtOAc/ hexane to provide 15-deoxy-PGE2 methyl ester 35 (36 mg, 74%) as a colorless oil. Rf = 0.13 (20% EtOAc/hexane); IRvmax (neat, cm−1): 3463, 2926, 2954, 2855, 1741, 1458, 1244, 1158, 1078, 967; 1H NMR (400 MHz, CDCl3): δ 0.86 (3H, t, J = 6.8 Hz), 1.23−1.37 (8H, m), 1.61−1.69 (3H, m), 2.00−2.09 (5H, m), 2.17 (1H, dd, J = 18.4, 9.6 Hz), 2.26−2.37 (5H, m), 2.71 (1H, dd, J = 18.4, 7.2 Hz), 3.64 (3H, s), 4.00−4.06 (1H, m), 5.26−5.41 (3H, m), 5.62 (1H, dt, J = 15.2, 6.8 Hz); 13C NMR (100 MHz, CDCl3): δ 14.1 (CH3), 22.6 (CH2), 24.7 (CH2), 24.9 (CH2), 26.6 (CH2), 28.8 (CH2), 29.3 (CH2), 31.7 (CH2), 32.6 (CH2), 33.4 (CH2), 46.2 (CH2), 51.5 (CH3), 53.8 (CH), 54.6 (CH), 72.3 (CH), 126.6 (CH), 129.0 (CH), 130.8 (CH), 135.3 (CH), 174.1 (C), 214.5 (C); HRMS (ESI): calcd for [C21H34O4 + Na]+ 373.2355; found 373.2353. (±)-15-Dehydroxy-PGE2 (36). To a solution of the methyl ester 35 (21 mg, 0.060 mmol) in acetone (1.0 mL), was added porcine pancreatic lipase (PPL, EC 3.1.13, 179 mg) and phosphate buffer solution (NaH2PO4/Na2HPO4, 6 mL, pH 7) at room temperature. After stirring at room temperature for 11 h, the mixture was diluted with EtOAc (30 mL) and then acidified to pH 5 with 0.1 N HCl. The mixture was further stirred with saturated (NH4)2SO4 solution, and the product was extracted with EtOAc (30 mL × 3). The combined organic layer was dried over MgSO4, filtered off, and concentrated in vacuo. The residue was purified by flash column chromatography (gradient elution; 50−70% EtOAc/hexane) to provide the 15-deoxyPGE2 36 (17 mg, 85%) as a colorless oil. 36: Rf = 0.25 (60% EtOAc/ hexane); IRνmax (neat, cm−1): 3625−2661 (br), 3422, 3010, 2955, 2926, 2855, 1710, 1456, 1242,1158,1076, 966, 724; 1H NMR (400 MHz, CDCl3): δ 0.86 (3H, t, J = 7.2 Hz), 1.23−1.37 (8H, m), 1.66 (2H, pent, J = 7.2 Hz), 2.01−2.09 (5H, m), 2.17 (1H, dd, J = 18.4, 9.4 Hz), 2.26−2.37 (5H, m), 2.71 (1H, dd, J = 18.4, 7.2 Hz), 4.00−4.60 (1H, m), 5.26−5.41 (3H, m), 5.63 (1H, dt, J = 15.2, 6.8 Hz); 13C NMR (100 MHz, CDCl3): δ 14.1 (CH3), 22.6 (CH2), 24.4 (CH2), 24.9 (CH2), 26.5 (CH2), 28.8 (CH2), 29.3 (CH2), 31.7 (CH2), 32.6 (CH2), 33.3 (CH2), 46.1 (CH2), 53.8 (CH), 54.6 (CH), 72.3 (CH), 126.7 (CH), 128.9 (CH), 130.6 (CH), 135.4 (CH), 178.9 (C), 214.6 (C); HRMS (ESI): calcd for [C20H32O4 + Na]+ 359.2193; found 359.2191. Deuterium Labeling Experiment for HADCA Reaction (Scheme 7). To a mixture of E-octen-1-yl-1-iodide (107 mg, 0.448 mmol), LiBr (78 mg, 0.895 mmol), and NaBr (5 mg, 0.045 mmol) in THF (4.5 mL) was added tert-butyl lithium (1.72 M in pentane, 520 mL, 0.895 mmol) at −78 °C over 10 min under argon atmosphere. The reaction mixture was stirred for at −78 °C for another 15 min. (Note: tert-butyl lithium with THF forms a bright yellow complex at −78 °C). The excess tert-butyl lithium was removed by addition of one or two drops of vinyl iodide to the reaction mixture. To this solution was added tert-butyl ester of silylvinyl sulfone rac-17 (80 mg, 0.179 mmol) in THF (1.5 mL). The resulting mixture was warmed to −50 °C in 0.5 h and stirred for 2 h at −50 °C. The reaction mixture was quenched with D2O (0.5 mL in THF 4 mL) at −50 °C and stirred for 15 min. The reaction mixture was poured into icecooled saturated solution of NH4Cl (30 mL) and extracted with EtOAc (10 mL × 3). The combined organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography (gradient elution; 8% to 20% EtOAc/hexane) provided the tert-butyl silylvinyl sulfone rac-17 (16 mg, 30%), cyclopentanone 25b (17 mg, 20%) and α,α-diD-24b. (30 mg, 30%) as a colorless oil. Compound α,α-di-D-24b: Rf = 0.50 (20% EtOAc/ hexane); IRvmax (neat, cm−1): 3069, 2975, 2927, 2855, 1730, 1587; 1H NMR (400 MHz, CDCl3): δ 0.35 (3H, s), 0.37 (3H, s), 0.86 (3H, t, J = 6.8 Hz), 1.22-.126 (9H, m), 1.38 (9H, s), 1.846−1.853 (2H, m), 2.18 (1H, ABq, d, J = 15.4, 7.6 Hz), 2.28 (1H, ABq, d, J = 15.4, 5.6 Hz), 2.64 (1H, dd, J = 8.8, 3.6 Hz), 2.97 (0.07H, d, J = 9.2 Hz), 3.20 (0.07H, d, J = 4.0 Hz), 4.19−4.23 (1H, m), 5.05 (1H, ddt, J = 15.2, 8.8, 1.2 Hz), 5.28 (1H, dt, J = 15.2, 6.4 Hz), 7.31−7.37 (3H, m), 7.46−7.53 (4H, m), 7.56−7.60 (1H, m), 7.73−7.76 (2H, m); 13C NMR (100 MHz, CDCl3): δ −1.4 (CH3), −1.2 (CH3), 14.1 (CH3), 22.6 (CH2 × 2), 28.1 (CH3 × 3), 28.8 (CH2), 28.9 (CH2), 31.7 (CH2), 32.5 (CH2), 40.4 (CH2), 43.1 (CH), 71.9 (CH), 80.7 (C),

Aldol/HADCA/Cyclization with octen-1-yl Lithium. To a solution of diisopropylamine (59 mg, 0.58 mmol), LiBr (210 mg, 2.42 mmol), NaBr (12 mg, 0.12 mmol) in THF (5.0 mL) was added n-BuLi (2.45 M in hexanes, 0.238, 0.581 mmol) at 0 °C under argon atmosphere with stirring for 15 min. The solution was cooled to −78 °C, and then tert-butyl acetate 31 (62 mg, 0.53 mmol) in THF (0.5 mL) was added dropwise with stirring at −78 °C for 1 h. To the mixture of LDA and tert-butyl acetate was added a solution of aldehyde 30 (150 mg, 0.484 mmol) in THF (0.5 mL) dropwise, and this mixture A was stirred for 30 min at −78 °C. In a separate vessel, a solution of vinyl iodide (230 mg, 0.968 mmol) in THF (5.0 mL) was mixed with tert-butyl lithium (1.65 M in pentane, 1.17 mL, 1.94 mmol) at −78 °C over 10 min under argon atmosphere. This reaction mixture was stirred at −78 °C for an additional 15 min, and the resulting vinyl lithium was added into the mixture A containing LDA/tert-butyl acetate/aldehyde via a cannula. The resulting mixture was gradually warmed to −20 °C in 1 h and stirred for 11 h at −20 °C. The reaction mixture was poured into ice-cooled saturated solution of NH4Cl (50 mL). The aqueous layer was extracted with EtOAc (10 mL × 3). The combined organic layer was washed with brine, dried over MgSO4, filtered off, and concentrated in vacuo. The residue was purified by flash column chromatography to provide the cyclopentanone 25b (125 mg, 53%) as a colorless oil. Aldol/HADCA/Cyclization with octyn-1-yl Lithium. To a mixture of diisopropylamine (59 mg, 2.45 mmol) and NaBr (12 mg, 0.121 mmol) in THF (5.0 mL) was added n-BuLi (2.45 M in hexanes, 0.238 mL, 0.581 mmol) at 0 °C under argon atmosphere with stirring for 15 min. The solution was cooled to −78 °C, to which was added tert-butyl acetate 31 (62 mg, 0.532 mmol) in THF (0.5 mL) dropwise with stirring at −78 °C for 1 h. To this solution (LDA/tert-butyl acetate) was added a solution of aldehyde 30 (160 mg, 0.484 mmol) in THF (0.5 mL) dropwise, and the stirring was continued for 30 min at −78 °C to name as solution A. A mixture of octyne (107 mg, 0.968 mmol) in THF and MeLi·LiBr complex (2.21 M in Et2O, 0.438 mL, 0.968 mmol) was kept at −78 °C for 1 h under argon atmosphere. This mixture (lithium acetylide solution) was added to the solution A of LDA/tert-butyl acetate/aldehyde via a cannula. The resulting mixture was warmed to −20 °C in 1 h and stirred for additional 4 h at −20 °C. The reaction mixture was poured into ice-cooled saturated solution of NH4Cl (50 mL). The aqueous layer was extracted with EtOAc (10 mL × 3). The combined organic layer was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography to obtain the cyclopentanone 25c (135 mg, 58%) as a colorless oil. (±)-15-Dehydroxy-PGE2 Methyl Ester (35) (Scheme 6). To a solution of 25b (102 mg, 0.211 mmol) and 13 (103 mg, 0.467 mmol) in DMF (2.1 mL) were added K2CO3 (17 mg, 0.127 mol) and NaI (3 mg, 0.021 mol) successively. The reaction mixture was stirred at room temperature for 40 min before pouring into H2O (20 mL) and extracted with Et2O (10 mL × 3). The combined organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The crude allylation product was obtained (33), which was used for next step without further purification. A solution of allylation crude product 33 in a mixture of MeOH (90 μL) and dry THF (0.9 mL) was added a solution of SmI2 (0.1 M in THF, 10.0 mL) dropwise at −78 °C. The resulting solution was stirred for 15 min at −78 °C, during which time the deep blue color of the solution faded. The solution was quenched with saturated solution of NH4Cl (10 mL), and the aqueous phase was extracted with Et2O (10 mL × 3). The combined organic layer was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (gradient elution by 5−15% EtOAc/hexane, 10% EtOAc/hexane, Rf = 0.5) to yield 34 (67 mg, 66% in two steps) as a colorless oil. To a solution of 34 (67 mg, 0.138 mmol) in THF (2.0 mL) was added 70% hydrogen fluoride−pyridine complex (22 μL) at 0 °C. The mixture was stirred at 0 °C for 1 h before pouring into saturated aqueous NaHCO3 (10 mL). The aqueous mixture was extracted with Et2O (10 mL × 3). The combined organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was J

DOI: 10.1021/acs.joc.5b02735 J. Org. Chem. XXXX, XXX, XXX−XXX

Article

The Journal of Organic Chemistry 125.6 (CH), 127.8(CH × 2), 128.1 (CH × 2), 129.0 (CH × 2), 129.7 (CH), 133.3 (CH), 133.5 (CH × 2), 135.7 (CH), 137.6 (C), 140.0 (C), 170.2 (C); HRMS (ESI): calcd for [C31H44D2O5SSi + Na]+ 583.2856; found 583.2853. General Procedure for Samarium(II) Iodide-Mediated Reformatsky-Type Reaction (Table 2). The starting materials 37a, 37b, 37c, 37d, and 19 were prepared according to literature.36,39−42 The following description provides a typical experimental procedure for the Reformatsky-type reaction of a chiral 3-bromoacetyl-2oxazolidinone (37a−d and 19) using 19 with aldehyde 20 as an example. To a solution of alcohol 21 (704 mg, 4.29 mmol) in DCM (42 mL, was added MnO2 (2.80 g, 32.2 mmol) at room temperature. The reaction mixture was stirred for 2 h and filtered. The filtrates were dried over MgSO4 and concentrated in vacuo to obtain the crude aldehyde product 20. Since this aldehyde is rather unstable, it is recommended to go successively to the next step. Under the argon atmosphere, samarium powder (1.21 mg, 8.04 mmol) in THF (11 mL) was placed in an Schlenk tube equipped with a magnetic stirring bar. To this solution was added diiodomethane (1.44 g, 5.36 mmol). The mixture was stirred for 2 h at room temperature, and SmI2 solution was obtained as a deep blue solution. The Schlenk tube was cooled to −78 °C, and a mixture of aldehyde 20 and chiral 3-bromoacetyl-2-oxazolidinone 19 (863 mg, 2.15 mmol) in dry THF (8.0 mL) was injected over a period of 10 min. The resulting solution was stirred at −78 °C for 0.5 h, during which time the deep green color of the solution faded. The reaction was quenched by addition of 25 mL of saturated solution of NH4Cl, and the aqueous phase was extracted with three 20 mL portions of diethyl ether. The combined organic layer was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography to provide the alcohol 18 (911 mg, 88%) as a colorless oil. (S)-3-((R)-3-Hydroxy-5-(phenylthio)pent-4-ynoyl)-4-isopropyl-5,5diphenyloxazolidin-2-one ((R)-18). Rf = 0.13 (20% EtOAc/hexane); IRvmax (neat, cm−1): 3470, 3060, 2966, 1784, 1703, 1582, 1530; 1H NMR (400 MHz, CDCl3): δ 0.75 (3H, d, J = 6.8 Hz), 0.88 (3H, d, J = 7.2 Hz), 1.97 (1H, qqd, J = 7.2, 6.8, 3.2 Hz), 3.08 (1H, d, J = 6.8 Hz), 3.26 (1H, ABq, d, J = 17.5, 7.2 Hz), 3.43 (1H, ABq, d, J = 17.5, 4.0 Hz), 5.00 (1H, ddd, J = 7.2, 6.8, 4.0 Hz), 5.38 (1H, d, J = 3.2 Hz), 7.19−7.23 (1H, m), 7.25−7.46 (14H, m); 13C NMR (100 MHz, CDCl3): δ 16.2 (CH3), 21.7 (CH3), 29.8 (CH), 42.7 (CH2), 59.5 (CH), 64.5 (CH), 72.3 (C), 89.8 (C), 97.8 (C), 125.5 (CH × 2), 125.8 (CH × 2), 126.2 (CH × 2), 126.5 (CH), 128.0 (CH), 128.3 (CH × 2), 128.7 (CH), 128.9 (CH × 2), 129.2 (CH × 2), 132.1 (C), 137.8 (C), 141.8 (C), 152.8 (C), 170.5 (C); HRMS (ESI): calcd for [C29H27O4NS + Na]+ 508.1553; found 508.1553. [α]26 D −122.9° (c 0.75, CHCl3). (S)-3-((R)-3-Hydroxy-5-(phenylthio)pent-4-ynoyl)-4-isopropyloxazolidin-2-one ((R)-38a) and (S)-3-((S)-3-Hydroxy-5-(phenylthio)pent-4-ynoyl)-4-isopropyloxazolidin-2-one ((S)-38a). (R)-/(S)-38a. According to the general procedure, 37a (202 mg) was converted to (R)-/(S)-38a (194 mg) in 72% yield as a colorless oil (entry 1, Table 2). Column chromatography afforded pure diastereomer fraction of (R)-38a (82 mg) and (S)-38a (28 mg) and unseparable mixture (84 mg) . (R)-38a: Rf = 0.20 (30% EtOAc/hexane); IRvmax (neat, cm−1): 3474, 3059, 2964, 2928, 2876, 1781, 1701, 1582; 1H NMR (400 MHz, CDCl3): δ 0.86 (3H, d, J = 6.0 Hz), 0.90 (3H, d, J = 6.8 Hz), 2.32−2.40 (1H, m), 3.20 (1H, d, J = 6.0 Hz), 3.39 (1H, ABq, d, J = 17.6, 4.0 Hz), 3.52 (1H, ABq, d, J = 17.6, 7.6 Hz), 4.21 (1H, ABq, d, J = 8.8, 3.2, Hz), 4.26 (1H, ABq, d, J = 8.8, 8.8 Hz), 4.43 (1H, ddd, J = 8.8, 4.0, 3.2 Hz), 5.05 (1H, ddd, J = 7.6, 6.0, 4.0 Hz), 7.18−7.22 (1H, m), 7.29−7.33 (2H, m), 7.38−7.41 (2H, m); 13C NMR (100 MHz, CDCl3): δ 14.6 (CH3), 17.8 (CH3), 28.4 (CH), 42.8 (CH2), 58.4 (CH), 59.4 (CH), 63.7 (CH2), 72.3 (C), 97.9 (CH), 126.3 (CH × 2), 126.6 (CH), 129.2 (CH × 2), 132.1 (C), 153.9 (C), 170.6 (C); HRMS (ESI): calcd for [C17H19NO4S + Na]+ 356.0927; found 356.0928; [α]24 D +63.2°(c 1.80, CHCl3). (S)38a: Rf = 0.28 (30% EtOAc/hexane); IRvmax (neat, cm−1): 3457, 3061, 2964, 2928, 2876, 1780, 1697; 1H NMR (400 MHz, CDCl3): δ 0.83 (3H, d, J = 7.0 Hz), 0.88 (3H, d, J = 7.0 Hz), 2.31−2.39 (1H, m), 3.28

(1H, dd, J = 17.4, 4.2 Hz), 3.62 (1H, dd, J = 17.4, 7.4 Hz), 4.20 (1H, ABq, d, J = 9.2, 3.2 Hz), 4.26 (1H, ABq, d, J = 9.2, 9.2 Hz), 4.43 (1H, ddd, J = 9.2, 3.6, 3.2 Hz), 5.01 (1H, dd, J = 7.4, 4.2 Hz), 7.18− 7.21 (1H, m), 7.28−7.32 (2H, m), 7.37−7.39 (2H, m); 13C NMR (100 MHz, CDCl3): δ 14.6 (CH3), 17.8 (CH3), 28.4 (CH), 42.8 (CH), 58.4 (CH), 59.6 (CH), 63.7 (CH2), 72.4 (C), 97.9 (C), 126.3 (CH × 2), 126.6 (CH), 129.2 (CH × 2), 132.1 (C), 153.9 (C), 170.8 (C); HRMS (ESI): calcd for [C17H19NO4S + Na]+ 356.0927; found 356.0927; [α]24 D +38.1° (c 1.20, CHCl3). (S)-4-Benzyl-3-((R)-3-hydroxy-5-(phenylthio)pent-4-ynoyl)oxazolidin-2-one ((R)-38b) and (S)-4-Benzyl-3-((S)-3-hydroxy-5(phenylthio)pent-4-ynoyl)oxazolidin-2-one ((S)-38b). ((R)-/(S)38b). According to the general procedure, 37b (223 mg) was converted to (R)-/(S)-38b (208 mg) in 73% yield as a colorless oil (entry 2, Table 2). Column chromatography afforded pure diastereomer fraction of (R)-38b (117 mg) and (S)-38b (26 mg) and unseparable mixture (65 mg). (R)-38b: Rf = 0.15 (30% EtOAc/hexane); IRvmax (neat, cm−1): 3460, 2922, 1781, 1582; 1H NMR (400 MHz, CDCl3): δ 2.78 (1H, dd, J = 13.2, 9.6 Hz), 3.28 (1H, dd, J = 13.2, 3.2 Hz), 3.40 (1H, ABq, d, J = 17.6, 4.0 Hz), 3.54 (1H, ABq, d, J = 17.6, 7.2 Hz), 4.15−4.22 (2H, m), 4.68 (1H, dddd, J = 9.6, 6.8, 3.6, 3.2 Hz), 5.09 (1H, br), 7.17− 7.21 (3H, m), 7.26−7.34 (5H, m), 7.38−7.42 (2H, m); 13C NMR (100 MHz, CDCl3): δ 37.7 (CH2), 42.9 (CH2), 55.0 (CH), 59.3 (CH), 66.4 (CH2), 72.5 (C), 97.9 (C), 126.3 (CH × 2), 126.6 (CH), 127.4 (CH), 128.9 (CH × 2), 129.2 (CH × 2), 129.3 (CH × 2), 132.0 (C), 134.9 (C), 153.2 (C), 170.6 (C); HRMS (ESI): calcd for [C21H19NO4S + Na]+ 404.0927; found 404.0929; [α]27 D +49.9° (c 0.90, CHCl3). (S)-38b: Rf = 0.20 (30% EtOAc/hexane); IRvmax (neat, cm−1): 3464, 3060, 3027, 2923, 2354, 1781, 1698; 1H NMR (400 MHz, CDCl3): δ 2.77 (1H, dd, J = 13.2, 9.6 Hz), 3.26 (1H, dd, J = 13.2, 3.2 Hz), 3.32 (1H, dd, J = 17.6, 4.4, Hz), 3.63 (1H, dd, J = 17.6, 7.2), 4.16 (1H, ABq, d, J = 9.2, 3.2 Hz), 4.21 (1H, ABq, d, J = 9.2, 8.8, Hz), 4.66−4.72 (1H, m), 5.06 (1H, br), 7.16−7.23 (3H, m), 7.25−7.33 (5H, m), 7.40−7.42 (2H, m); 13C NMR (100 MHz, CDCl3): δ 37.7 (CH2), 42.8 (CH2), 55.0 (CH), 59.5 (CH), 66.4 (CH2), 72.6 (C), 97.8 (C), 126.4 (CH × 2), 126.7 (CH), 127.4 (CH), 129.0 (CH), 129.2 (CH), 129.4 (CH), 132.0 (C), 134.8 (C), 153.3 (C), 170.8 (C); HRMS (ESI): calcd for [C21H19NO4S + Na]+ 404.0927; found 404.0927; [α]26 D +28.8° (c 1.0, CHCl3). (S)-3-((R)-3-Hydroxy-5-(phenylthio)pent-4-ynoyl)-4-isopropyl-5,5dimethyloxazolidin-2-one ((R)-38c) and (S)-3-((S)-3-Hydroxy-5(phenylthio)pent-4-ynoyl)-4-isopropyl-5,5-dimethyloxazolidin-2one ((S)-38c). ((R)-/(S)-38c). According to the general procedure, 37c (225 mg) was converted to (R)-/(S)-38c (226 mg) in 77% yield as a colorless oil (entry 3, Table 2). Column chromatography afforded pure diastereomer fraction of (R)-38c (75 mg) and (S)-38c (89 mg) and unseparable mixture (62 mg). (R)-38c: Rf = 0.10 (20% EtOAc/ hexane); IRvmax (neat, cm−1): 3452, 2974, 1776, 1702, 1582; 1H NMR (400 MHz, CDCl3): δ 0.93 (3H, d, J = 6.8 Hz), 1.02 (3H, d, J = 6.8 Hz), 1.34 (3H, s), 1.49 (3H, s), 2.09−2.17 (1H, m), 3.23 (1H, br), 3.38 (1H, ABq, d, J = 17.2, 4.0 Hz), 3.58 (1H, ABq, d, J = 17.2, 7.2 Hz), 4.15 (1H, d, J = 3.6 Hz), 5.04 (1H, br), 7.18−7.22 (1H, m), 7.29−7.33 (2H, m), 7.38−7.40 (2H, m); 13C NMR (100 MHz, CDCl3): δ 17.0 (CH3), 21.3 (CH3), 21.5 (CH3), 28.7 (CH3), 29.5 (CH), 42.6 (CH2), 59.9 (CH), 66.5 (CH), 72.5 (C), 83.4 (C), 97.8 (C), 126.36 (CH × 2), 126.39 (CH), 129.2 (CH × 2), 129.4 (C), 132.1 (C), 153.4 (C), 171.4 (C); HRMS (ESI): calcd for [C19H23NO4S + Na]+ 384.1240; found 384.1243; [α]25 D +29.9° (c 0.85, CHCl3). (S)-38c: Rf = 0.15 (20% EtOAc/hexane); IRvmax (neat, cm−1): 3463, 3059, 2973, 1774, 1701, 1582; 1H NMR (400 MHz, CDCl3): δ 0.92 (3H, d, J = 6.8 Hz), 1.00 (3H, d, J = 6.8 Hz), 1.37 (3H, s), 1.49 (3H, s), 2.08−2.16 (1H, m), 3.31 (1H, ABq, d, J = 17.2, 4.4 Hz), 3.36 (1H, br), 3.64 (1H, ABq, d, J = 17.2, 7.6 Hz), 4.15 (1H, d, J = 3.2 Hz), 5.02 (1H, br), 7.17−7.21 (1H, m), 7.28−7.32 (2H, m), 7.38−7.40 (2H, m); 13C NMR (100 MHz, CDCl3): δ 16.9 (CH3), 21.3 (CH3), 21.5 (CH3), 28.7 (CH), 29.5 (CH3), 42.7 (CH2), 59.7 (CH), 66.4 (CH), 72.4 (C), 83.3 (C), 97.9 (C), 126.3 (CH × 2), 126.6 (CH), 129.2 (CH × 2), 132.0 (C), 153.4 (C), 171.3 (C), HRMS (ESI): calcd for [C19H23NO4S + Na]+ 384.1240; found 384.1242; [α]26 D +17.1° (c 1.10, CHCl3). K

DOI: 10.1021/acs.joc.5b02735 J. Org. Chem. XXXX, XXX, XXX−XXX

Article

The Journal of Organic Chemistry

The residue was purified by flash chromatography (10% EtOAc/ hexane) to provide the ester (R)-22 (43 mg, 50% over two steps) as a colorless oil. (R)-22: Rf = 0.3 (10% EtOAc/hexane); IRvmax (neat, cm−1): 3435, 3060, 2978, 2931, 1726, 1583; 1H NMR (400 MHz, CDCl3): δ 1.45 (9H, s), 2.72−2.73 (2H, m), 3.38 (1H, br), 4.89 (1H, dd, J = 5.2, 5.2 Hz), 7.18−7.21 (1H, m), 7.28−7.32 (2H, m), 7.38− 7.40 (2H, m); 13C NMR (100 MHz, CDCl3): δ 28.1 (CH3 × 3), 42.7 (CH2), 59.8 (CH), 72.1 (C), 82.0 (C), 98.0 (C), 126.3 (CH × 2), 126.6 (CH), 129.2 (CH), 132.2 (C), 170.6 (C); HRMS (ESI): calcd for [C15H18O3S + Na]+ 301.0869, found 301.0869. [α]25 D +3.12° (c 1.16, CHCl3) tert-Butyl (S)-3-hydroxy-5-(phenylthio)pent-4-ynoate ((S)-22). According to the general procedure, (S)-38a (57 mg) was converted to (S)-22 (23 mg, 48% yield in two steps) as a colorless oil. The NMR spectrum was identical to (R)-22, and the specific rotation (S)-22 was [α]28 D −3.1° (c 1.65, CHCl3). (R,Z)-tert-Butyl 5-(dimethyl(phenyl)silyl)-3-hydroxy-5(phenylthio)pent-4-enoate ((R)-17). The dicobalthexacarbonyl complex of 2-methyl-butyn-2-ol (0.5 M in DCM, 0.17 mL, 0.085 mmol) was added to a mixture of the solution of thiophenylacetylene (R)-22 (236 mg, 0.848 mmol) and dimethylphenyl silane (0.128 mg, 0.933 mmol) in dry 1,2-dichloroethane (8.4 mL) and then heated to 80 °C and stirred for 2 h. After the reaction mixture was cooled to room temperature, the solvent was removed in vacuo. The residue was washed with cold TBAF and brine and then purified by chromatography (10% EtOAc/hexane) to afford vinylsilane (R)-23 (292 mg, 87%) as a colorless liquid. The vinylsilane (R)-23 (292 mg, 0.740 mmol) in DCM (7.4 mL) was added m-CPBA (457 mg, 1.85 mmol, 70% of purity) and NaHCO3 (310 mg, 3.70 mmol) at 0 °C and stirred 1 h. The reaction mixture was quenched with 1 N Na2S2O3 (10 mL). The aqueous layer was extracted with DCM (10 mL × 3). The combined organic layer was washed with 1 N NaHCO3 solution (10 mL), dried over MgSO4, and filtered off, and concentrated in vacuo. The residue was purified by flash chromatography (20% EtOAc/hexane) to yield the (R)-silylvinyl sulfone (R)-17 (297 mg, 90% over two steps) as a white solid. (R)-17: Mp: 67−68 °C (recrystallization from EtOAc/hexane); Rf = 0.25 (20% EtOAc/hexane); IRvmax (neat, cm−1): 3494, 3070, 3002, 2978, 2929, 2852, 1726, 1590; 1H NMR (400 MHz, CDCl3): δ 0.52 (6H, s), 1.41 (9H, s), 2.42 (1H, ABq, d, J = 16.8, 8.0 Hz), 2.51 (1H, ABq, d, J = 16.8, 4.0 Hz), 3.51 (1H, br), 5.37 (1H, ddd, J = 8.0, 8.0, 4.0 Hz), 7.28−7.36 (5H, m), 7.42−7.48 (3H, m), 7.55−7.57 (2H, m); 13C NMR (100 MHz, CDCl3): δ −2.1 (CH3), −2.0 (CH3), 28.1 (CH3 × 3), 41.1 (CH2), 65.6 (CH), 81.8 (C), 127.0 (CH × 2), 128.0 (CH × 2), 128.9 (CH × 2), 129.8 (CH), 133.0 (CH), 134.4 (CH × 2), 135.1 (C), 142.1 (C), 145.6 (C), 157.7 (CH), 171.2 (C); HRMS (ESI): calcd for [C23H30O5SSi + Na]+ 469.1475; found 469.1475. [α]25 D +50.4° (c 1.10, CHCl3). (2R,3S,4R)-3-((S,E)-3-((tert-Butyldimethylsilyl)oxy)oct-1-en-1yl)-4-((dimethyl(phenyl)silyl)oxy)-2-(phenylsulfonyl)cyclopentanone ((−)-14). Compound 15 was synthesized according to the literature procedure.33 To the (S)-vinyl iodide 15 (255 mg, 0.693 mmol), LiBr (100 mg, 1.16 mmol) in Et2O (0.69 mL) was added tert-butyl lithium (1.65 M in pentane, 0.84 mL, 1.39 mmol) at −78 °C over 10 min under argon atmosphere. After this reaction mixture was stirred at −78 °C for additional 15 min, a small amount of THF (0.3 mL) was added as indicator to observe color change; thus, tert-butyl lithium in THF forms a bright yellow complex at −78 °C. The excess tert-butyl lithium was removed by addition of one or two drops of (S)-vinyl iodide 15 to the reaction mixture. To this solution was added (R)-silyl-vinyl phenyl sulfone (R)-17 (103 mg, 0.231 mmol) in Et2O (0.20 mL). The resulting mixture was warmed to −20 °C in 1 h and stirred for further 11 h at −20 °C. The reaction mixture was poured into ice-cold saturated solution of NH4Cl (20 mL). The aqueous layer was extracted with EtOAc (10 mL × 3). The combined organic layer was washed with brine, dried over MgSO4, filtered off, and concentrated in vacuo. The residue was purified by flash column chromatography (7% EtOAc/hexane) to afford the cyclopentanone (−)-14 (82 mg, 58%) as a colorless oil. (−)-14: Rf = 0.33 (10% EtOAc/hexane); IRvmax (neat, cm−1): 3034, 2996, 2977, 2928, 1726, 1590; 1H NMR (400 MHz, CDCl3): δ 0.00 (3H, s), 0.03 (3H, s),

(S)-4-Benzyl-3-((R)-3-hydroxy-5-(phenylthio)pent-4-ynoyl)-5,5-dimethyloxazolidin-2-one ((R)-38d) and (S)-4-Benzyl-3-((S)-3-hydroxy-5-(phenylthio)pent-4-ynoyl)-5,5-dimethyloxazolidin-2-one ((S)-38d). ((R)-/(S)-38d). According to the general procedure, 37d (323 mg) was converted to 38d (363 mg) in 90% yield as colorless oil (entry 4, Table 2). Column chromatography afforded pure diastereomer fraction of (R)-38d (80 mg) and (S)-38d (43 mg) and unseparable mixture (240 mg). (R)-38d): Rf = 0.30 (30% EtOAc/ hexane); IRvmax (neat, cm−1): 3449, 3060, 2980, 2928, 1783, 1697, 1582; 1H NMR (400 MHz, CDCl3): δ 1.32 (3H, s), 1.36 (3H, s), 2.86 (1H, dd, J = 14.4, 9.2 Hz), 3.12 (1H, dd, J = 14.4, 4.4 Hz), 3.31 (1H, dd, J = 17.2, 4.0 Hz), 3.57 (1H, dd, J = 17.2, 7.6 Hz), 4.51 (1H, dd, J = 9.2, 4.4 Hz), 4.99 (1H, br), 7.18−7.24 (2H, m), 7.26−7.33 (5H, m), 7.39−7.4 (2H, m); 13C NMR (100 MHz, CDCl3): δ 22.1 (CH3), 28.4 (CH3), 35.3 (CH2), 42.8 (CH2), 59.6 (CH), 63.4 (CH), 72.5 (C), 82.8 (C), 97.8 (C), 126.4 (CH × 2), 126.6 (CH), 126.9 (CH), 128.7 (CH × 2), 129.0 (CH × 2), 129.2 (CH × 2), 132.1 (C), 136.6 (C), 152.4 (C), 171.0 (C); HRMS (ESI): calcd for [C23H23NO4S + Na]+ 432.1240; found 432.1240. [α]25 D −12.5° (c 1.60, CHCl3). (S)-38d): Rf = 0.38 (30% EtOAc/hexane); IRvmax (neat, cm−1): 3471, 3062, 3029, 2981, 2926, 1783, 1694, 1582; 1H NMR (400 MHz, CDCl3): δ 1.35 (3H, s), 1.36 (3H, s), 2.84 (1H, dd, J = 14.4, 9.2 Hz), 3.10−3.15 (2H, m), 3.34 (1H, ABq, d, J = 17.6, 4.0 Hz), 3.56 (1H, ABq, d, J = 17.6, 7.2 Hz), 4.51 (1H, dd, J = 9.6, 9.2 Hz), 4.99 (1H, ddd, J = 7.2, 6.8, 4.0 Hz), 7.14−7.18 (1H, m), 7.22−7.31 (7H, m), 7.38−7.40 (2H, m); 13C NMR (100 MHz, CDCl3): δ 22. (CH3), 28.5 (CH3), 35.3 (CH2), 43.0 (CH2), 59.5 (CH), 63.5 (CH), 72.6 (C), 82.7 (C), 97.7 (C), 126.4 (CH × 2), 126.6 (CH), 126.9 (CH), 128.7 (CH × 2), 129.0 (CH × 2), 129.2 (CH × 2), 132.1 (C), 136.6 (C), 152.4 (C), 171.1 (C); HRMS (ESI): calcd for [C23H23NO4S + Na]+ 432.1240; found 432.1242. [α]24 D −34.4°(c 1.55, CHCl3). After the absolute configurations of 38a were determined by Mosher− Kusumi protocol,44 the rest amount [(R)-38a and (S)-38a] were separated by column chromatography. Then hydrolysis of each of them gave the corresponding free carboxylic acid, and was further converted to tert-butyl ester (R)-22 and (S)-22, respectively. The (R)-22 exhibits a positive specific rotation, and (S)-22 exhibits a negative specific rotation. Absolute configurations of the alcoholic carbon in the β-hydroxy carboximide (38b−d, 18) were assumed by converting them into the corresponding tert-butyl esters. From the sign of the specific rotations of the tert-butyl esters, the absolute configurations of those alcoholic carbons in each compound were assumed to be positive to the R and negative to the S configuration, respectively. General Procedure for Mosher Ester. To a solution of alcohol (172 mg, 0.51 mmol) in DCM (4.0 mL) at room temperature under argon were added (R)- or (S)-MTPA (158 mg, 0.77 mmol) and DCC (158 mg, 0.77 mmol), respectively. After stirring for 20 h, the reaction mixture was poured into ice-cold, saturated, aqueous NH4Cl. The aqueous layer was separated and extracted with DCM. The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography to give (S)-MTPA-(S)-38a (197 mg, 70%) and (R)-MTPA-(S)-38a, (182 mg, 65%) (see SI for the NMR spectra of the Mosher method). tert-Butyl (R)-3-hydroxy-5-(phenylthio)pent-4-ynoate ((R)22). To a mixture of lithium hydroxide monohydrate (33 mg, 0.780 mmol) in THF (3.0 mL) and H2O (1.0 mL) was added hydrogen peroxide (35% in H2O, 227 mL, 2.34 mmol) at 0 °C and stirred for 15 min. (R)-38a (119 mg, 0.312 mmol) in THF (1.0 mL) was then added into this lithium peroxide solution at 0 °C and stirred for 1.5 h. The reaction mixture was diluted with water (30 mL) and extracted with DCM (10 mL × 3). The DCM layers were combined and dried over MgSO4, and concentrated in vacuo to give an oxazolidone. Subsequently the aqueous solution was cooled to 0 °C, then acidified to pH = 1 by 1 N HCl and extracted with Et2O (10 mL × 3). The combined organic layers was dried over MgSO4, and concentrated in vacuo to afford the crude carboxyl acid (69 mg) as colorless oil. To the carboxylic acid (69 mg) in DCM (3.0 mL) was added tert-butyl-trichloroacetimidate (95 mg, 0.435 mmol) at room temperature. After 50 min, the solvent was evaporated in vacuo. L

DOI: 10.1021/acs.joc.5b02735 J. Org. Chem. XXXX, XXX, XXX−XXX

Article

The Journal of Organic Chemistry Notes

0.348 (3H, s), 0.359 (3H, s), 0.84−0.90 (12H, H), 1.24−1.44 (8H, m), 2.41 (1H, ABq, d, J = 17.2, 6.8 Hz), 2.48 (1H, ABq, d, J = 17.2, 10.0 Hz), 3.35−3.41 (1H, m), 3.49 (1H, d, J = 9.6 Hz), 3.94 (1H, ddd, J = 10.0, 7.2, 6.8 Hz), 4.03 (1H, td, J = 5.2, 4.8 Hz), 5.45 (1H, ABq, dd, J = 15.6, 7.6, 0.8 Hz), 5.57 (1H, ABq, d, J = 15.6, 4.8 Hz), 7.32−7.41 (3H, m), 7.49−7.55 (4H, m), 7.62−7.66 (1H, m), 7.81−7.83 (2H, m); 13 C NMR (100 MHz, CDCl3): δ −4.8 (CH3), −4.2 (CH3), −1.6 (CH3), −1.1 (CH3), 14.1 (CH3), 18.2 (C), 22.6 (CH2), 24.9 (CH2), 31.8 (CH2), 38.2 (CH2), 48.3 (CH2), 49.1 (CH), 71.8 (CH), 72.2 (CH), 74.5 (CH), 126.1 (CH), 128.0 (CH × 2), 129.1 (CH × 2), 129.2 (CH × 2), 130.0 (CH), 133.5 (CH × 2), 134.1 (CH), 136.8 (C), 137.8 (CH), 138.3 (C), 201.9 (C); HRMS (ESI): calcd for [C33H50O5SSi2 + Na]+ 637.2810; found 637.2811. [α]27 D −22.1° (c 1.20, CHCl3). PGE2 Methyl Ester ((−)-12). Allyl bromide 13 was obtained from propargyl alcohol in six steps according to literature procedure.43 To a solution of (−)-14 (64 mg, 0.104 mmol) and 13 (69 mg, 0.312 mmol) in DMF (1.5 mL) were successively added K2CO3 (10 mg, 0.072 mmol) and NaI (2 mg, 0.013 mmol), and the reaction mixture was stirred at room temperature. After 40 min, the reaction mixture was quenched with H2O (20 mL) and extracted with Et2O (10 mL × 3). The combined organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The crude allylation product 39 was used for next step without further purification. A solution of 39 and MeOH (90 μL) in dry THF (0.9 mL) was added SmI2 (0.1 M in THF, 3.0 mL) dropwise. The resulting solution was stirred at −78 °C for 15 min, during which time the deep green color of the solution faded. The solution was quenched with saturated solution of NH4Cl (10 mL), and the aqueous phase was extracted with Et2O (10 mL × 3). The combined organic layer was washed with brine, dried over MgSO4, filtered off, and concentrated in vacuo. The residues were purified by flash chromatography (gradient 5% to 20% EtOAc/hexane, 10% EtOAc/ hexane, Rf = 0.4) and provided an inseparable mixture of 40 and allyl bromide 13. A solution of mixture 40 and 13 in MeCN (2.0 mL) was added 70% hydrogen fluoride−pyridine complex (50 μL) at 0 °C. The mixture was stirred at 0 °C for 1 h before pouring into saturated aqueous NaHCO3 (5 mL). The aqueous solution was extracted with EtOAc (10 mL × 3). The combined organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residues were purified by flash chromatography (gradient 50 to 80% EtOAc/hexane) and provided PGE2 methyl ester (−)-12 (16 mg, 42% over three steps) as a colorless oil. (−)-12: Rf = 0.13 (70% EtOAc/hexane); IRvmax (neat, cm−1): 3421, 2930, 2857, 1743, 1735, 1437, 1457, 1437, 1247, 1160, 1080; 1H NMR (400 MHz, CDCl3): δ 0.88 (3H, t, J = 6.8 Hz), 1.23−1.70 (10H, m), 1.98−2.44 (9H, m), 2.73 (1H, dd, J = 18.4, 7.2 Hz), 3.65 (3H, s), 4.05−4.13 (2H, m), 5.28−5.42 (2H, m). 5.57 (1H, ABq, d, J = 15.2, 8.0 Hz), 5.67 (1H, ABq, d, J = 15.2, 6.4 Hz); 13C NMR (100 MHz, CDCl3): δ 14.0 (CH3), 22.6 (CH2), 24.7 (CH2), 25.1 (CH2), 25.2 (CH2), 26.6 (CH2), 31.7 (CH2), 33.4 (CH2), 37.4 (CH2), 46.2 (CH2), 51.6 (CH3), 53.3 (CH), 54.5 (CH), 72.2 (CH), 72.6 (CH), 126.5 (CH), 130.2 (CH), 130.9 (CH), 137.2 (CH), 174.2 (C), 214.1 (C); HRMS (ESI): calcd for [C21H34O5 + Na]+ 389.2298; found 389.2300. [α]24 D −65.9° (c 0.30, MeOH).

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The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank Ministry of Science and Technology (former National Science Council) Taiwan and National Tsing Hua University for financial supports of this work.

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DEDICATION Dedicated to Prof. Gilbert Stork of Columbia University on his 94th birthday.

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DOI: 10.1021/acs.joc.5b02735 J. Org. Chem. XXXX, XXX, XXX−XXX

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DOI: 10.1021/acs.joc.5b02735 J. Org. Chem. XXXX, XXX, XXX−XXX